ArticleGenome medicine2019
Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension.
Article in Genome medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 80 papers, 2 of them syntheses that pooled it.
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Who cites it
80 citing papers in PubMed, 2 syntheses or guidelines pooled it, 137 citations in OpenAlex.
- The prevalence of pathogenic variants in the BMPR2 gene in patients with the idiopathic pulmonary arterial hypertension in the Russian population: sequencing data and meta-analysis.Respiratory research · 2025Pooled it
- New progress in diagnosis and treatment of pulmonary arterial hypertension.Journal of cardiothoracic surgery · 2022Pooled it
- Trial
- Variant Class-Specific Phenotypes and Outcomes in Pediatric TBX4-Associated Pulmonary Hypertension.Pediatric pulmonology · 2026Article
- Germline and somatic variants in DNMT3A and other clonal haematopoiesis of indeterminate potential genes contribute to pulmonary arterial hypertension.European heart journal · 2026Article
- Genetic variants in pulmonary hypertension associated with chronic obstructive pulmonary disease.Current opinion in pulmonary medicine · 2026Review
- Rare T-box variants in adult pulmonary arterial hypertension with congenital heart disease.Journal of applied genetics · 2026Article
- Inherited TBX4 frameshifting variants predicted to escape nonsense mediated decay in two families with variable phenotypes, including lethal lung developmental disorders.Human genomics · 2026Article
- The Role of Genetics in Congenital Heart Disease-Associated Pulmonary Arterial Hypertension.Pediatric cardiology · 2026Observational
- Identifying Potential Drug Targets in Coronary Atherosclerosis: Insights from the Druggable Genome and Mendelian Randomization.Cardiovascular drugs and therapy · 2026Article
- Drug Discovery Strategies for Kallikrein-Related Peptidases.International journal of molecular sciences · 2025Review
- Macrophage plasticity and glucose metabolism: the role of immunometabolism in pulmonary arterial hypertension.Clinical science (London, England : 1979) · 2025Review
- BMP9 regulates the endothelial secretome to drive pulmonary hypertension.bioRxiv : the preprint server for biology · 2025Article
- TBX4 in Pulmonary Hypertension: Linking Lung Development to Precision Therapy.American journal of respiratory cell and molecular biology · 2025Article
- Loss ofAmerican journal of respiratory cell and molecular biology · 2025Article
- SOX17 in pulmonary arterial hypertension: from development to clinical phenotype.European respiratory review : an official journal of the European Respiratory Society · 2025Review
- Review
- 2025 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.Circulation · 2025Review
- Precision Medicine for Pulmonary Vascular Disease: The Future Is Now (2023 Grover Conference Series).Pulmonary circulation · 2025Article
- Candidate genes related to spiritual mediumship: a whole-exome sequencing analysis of highly gifted mediums.Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999) · 2025Article
20 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundGroup 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined.
methodsTo identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH (PAH Biobank, n = 2572). We then carried out rare deleterious variant identification followed by case-control gene-based association analyses. To control for population structure, only unrelated European cases (n = 1832) and controls (n = 12,771) were used in association tests. Empirical p values were determined by permutation analyses, and the threshold for significance defined by Bonferroni's correction for multiple testing.
resultsTissue kallikrein 1 (KLK1) and gamma glutamyl carboxylase (GGCX) were identified as new candidate risk genes for idiopathic PAH (IPAH) with genome-wide significance. We note that variant carriers had later mean age of onset and relatively moderate disease phenotypes compared to bone morphogenetic receptor type 2 variant carriers. We also confirmed the genome-wide association of recently reported growth differentiation factor (GDF2) with IPAH and further implicate T-box 4 (TBX4) with child-onset PAH.
conclusionsWe report robust association of novel genes KLK1 and GGCX with IPAH, accounting for ~ 0.4% and 0.9% of PAH Biobank cases, respectively. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms, and therapeutic targets for this lethal vasculopathy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.